One of the most striking manifestations of variability in cardiac electrophysiology is the apparently unpredictable development of the drug-induced or ~acquired~ long QT syndrome (ALQT) during antiarrhythmic therapy. ALQT, which can be fatal, occurs in up to 5% of exposed patients, even when risk factors such as pre- existing QT prolongation or hypokalemia are eliminated. The Project will combine clinical and molecular approaches to test the hypothesis that a subset of patients with ALQT is genetically predisposed to developing this adverse reaction to drug therapy. In Specific Aim 1, evidence for familial aggregation of ALQT susceptibility will be sought by challenging first degree relatives of ALQT probands with a low dose infusion of the action potential prolonging agent, ibutilide. The extent of QT prolongation in this test population will be compared with that in a control group, first degree relatives of patients who have tolerated chronic antiarrhythmic therapy. Recent advances in defining loci responsible for causing the congenital long QT syndrome have identified three cardiac ion channel genes (HERG, KvLQT1, SCN5A) as logical candidates for an ALQT susceptibility gene. Other cardiac ion channel genes (Kv1.5, Kv4.3, minK) that appear to have important roles in ventricular repolarization also candidates for this search. Specific Aim 2 will test the hypothesis that structural polymorphisms or allelic variation in DNA regulatory elements that segregate with the ALQT phenotype are present in these candidate genes; these experiments will also define the 5' end of the KvLQT1 coding sequence. Since variability in repolarization may also be acquired through variability in expression of ion channel genes, the goal of Specific Aim 3 is to identify transcriptional control sequences in HERG and in KvLQT1. The outcome of these studies will be a test of the concept that genetic factors play an important role in ALQT, and improved understanding of the molecular mechanisms determining variability in cardiac repolarization in human subjects.